Abstract
Meiotic recombination has a central role in the evolution of sexually reproducing organisms. The two recombination outcomes, crossover and non-crossover, increase genetic diversity, but have the potential to homogenize alleles by gene conversion. Whereas crossover rates vary considerably across the genome, non-crossovers and gene conversions have only been identified in a handful of loci. To examine recombination genome wide and at high spatial resolution, we generated maps of crossovers, crossover-associated gene conversion and non-crossover gene conversion using dense genetic marker data collected from all four products of fifty-six yeast (Saccharomyces cerevisiae) meioses. Our maps reveal differences in the distributions of crossovers and non-crossovers, showing more regions where either crossovers or non-crossovers are favoured than expected by chance. Furthermore, we detect evidence for interference between crossovers and non-crossovers, a phenomenon previously only known to occur between crossovers. Up to 1% of the genome of each meiotic product is subject to gene conversion in a single meiosis, with detectable bias towards GC nucleotides. To our knowledge the maps represent the first high-resolution, genome-wide characterization of the multiple outcomes of recombination in any organism. In addition, because non-crossover hotspots create holes of reduced linkage within haplotype blocks, our results stress the need to incorporate non-crossovers into genetic linkage analysis.
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ArrayExpress
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Raw data are available from ArrayExpress (http://www.ebi.ac.uk/arrayexpress) under accession number E-TABM-470.
References
Gordo, I. & Charlesworth, B. Genetic linkage and molecular evolution. Curr. Biol. 11, R684–R686 (2001)
Chen, J. M. et al. Gene conversion: mechanisms, evolution and human disease. Nature Rev. Genet. 8, 762–775 (2007)
Page, S. L. & Hawley, R. S. Chromosome choreography: the meiotic ballet. Science 301, 785–789 (2003)
Baudat, F. & de Massy, B. Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis. Chromosome Res. 15, 565–577 (2007)
Bishop, D. K. & Zickler, D. Early decision; meiotic crossover interference prior to stable strand exchange and synapsis. Cell 117, 9–15 (2004)
Whitby, M. C. Making crossovers during meiosis. Biochem. Soc. Trans. 33, 1451–1455 (2005)
Argueso, J. L., Wanat, J., Gemici, Z. & Alani, E. Competing crossover pathways act during meiosis in Saccharomyces cerevisiae . Genetics 168, 1805–1816 (2004)
Hollingsworth, N. M. & Brill, S. J. The Mus81 solution to resolution: generating meiotic crossovers without Holliday junctions. Genes Dev. 18, 117–125 (2004)
Allers, T. & Lichten, M. Differential timing and control of noncrossover and crossover recombination during meiosis. Cell 106, 47–57 (2001)
Baudat, F. & Nicolas, A. Clustering of meiotic double-strand breaks on yeast chromosome III. Proc. Natl Acad. Sci. USA 94, 5213–5218 (1997)
Gerton, J. L. et al. Inaugural article: global mapping of meiotic recombination hotspots and coldspots in the yeast Saccharomyces cerevisiae . Proc. Natl Acad. Sci. USA 97, 11383–11390 (2000)
Borde, V. et al. Association of Mre11p with double-strand break sites during yeast meiosis. Mol. Cell 13, 389–401 (2004)
Buhler, C., Borde, V. & Lichten, M. Mapping meiotic single-strand DNA reveals a new landscape of DNA double-strand breaks in Saccharomyces cerevisiae . PLoS Biol. 5, 2797–2808 (2007)
Blitzblau, H. G. et al. Mapping of meiotic single-stranded DNA reveals double-stranded-break hotspots near centromeres and telomeres. Curr. Biol. 17, 2003–2012 (2007)
Cherry, J. M. et al. Genetic and physical maps of Saccharomyces cerevisiae . Nature 387 (suppl.). 67–73 (1997)
McCusker, J. H., Clemons, K. V., Stevens, D. A. & Davis, R. W. Genetic characterization of pathogenic Saccharomyces cerevisiae isolates. Genetics 136, 1261–1269 (1994)
Mortimer, R. K. & Johnston, J. R. Genealogy of principal strains of the yeast genetic stock center. Genetics 113, 35–43 (1986)
Coop, G. et al. High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319, 1395–1398 (2008)
Borts, R. H. & Haber, J. E. Length and distribution of meiotic gene conversion tracts and crossovers in Saccharomyces cerevisiae . Genetics 123, 69–80 (1989)
Jeffreys, A. J. & May, C. A. Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nature Genet. 36, 151–156 (2004)
Terasawa, M. et al. Meiotic recombination-related DNA synthesis and its implications for cross-over and non-cross-over recombinant formation. Proc. Natl Acad. Sci. USA 104, 5965–5970 (2007)
Merker, J. D., Dominska, M. & Petes, T. D. Patterns of heteroduplex formation associated with the initiation of meiotic recombination in the yeast Saccharomyces cerevisiae . Genetics 165, 47–63 (2003)
Lichten, M. & Goldman, A. S. Meiotic recombination hotspots. Annu. Rev. Genet. 29, 423–444 (1995)
Martini, E., Diaz, R. L., Hunter, N. & Keeney, S. Crossover homeostasis in yeast meiosis. Cell 126, 285–295 (2006)
Ardlie, K. et al. Lower-than-expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion. Am. J. Hum. Genet. 69, 582–589 (2001)
Wall, J. D. Close look at gene conversion hot spots. Nature Genet. 36, 114–115 (2004)
Primig, M. et al. The core meiotic transcriptome in budding yeasts. Nature Genet. 26, 415–423 (2000)
Petes, T. D. Meiotic recombination hot spots and cold spots. Nature Rev. Genet. 2, 360–369 (2001)
Ross-Macdonald, P. & Roeder, G. S. Mutation of a meiosis-specific MutS homolog decreases crossing over but not mismatch correction. Cell 79, 1069–1080 (1994)
Kunz, C. & Schar, P. Meiotic recombination: sealing the partnership at the junction. Curr. Biol. 14, R962–R964 (2004)
Borner, G. V., Kleckner, N. & Hunter, N. Crossover/noncrossover differentiation, synaptonemal complex formation, and regulatory surveillance at the leptotene/zygotene transition of meiosis. Cell 117, 29–45 (2004)
Schwacha, A. & Kleckner, N. Interhomolog bias during meiotic recombination: meiotic functions promote a highly differentiated interhomolog-only pathway. Cell 90, 1123–1135 (1997)
Hillers, K. J. Crossover interference. Curr. Biol. 14, R1036–R1037 (2004)
Malkova, A. et al. Gene conversion and crossing over along the 405-kb left arm of Saccharomyces cerevisiae chromosome VII. Genetics 168, 49–63 (2004)
Oh, S. D. et al. BLM ortholog, Sgs1, prevents aberrant crossing-over by suppressing formation of multichromatid joint molecules. Cell 130, 259–272 (2007)
Hurles, M. How homologous recombination generates a mutable genome. Hum. Genomics 2, 179–186 (2005)
Birdsell, J. A. Integrating genomics, bioinformatics, and classical genetics to study the effects of recombination on genome evolution. Mol. Biol. Evol. 19, 1181–1197 (2002)
Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993)
Kleckner, N. et al. A mechanical basis for chromosome function. Proc. Natl Acad. Sci. USA 101, 12592–12597 (2004)
Borts, R. H. & Haber, J. E. Meiotic recombination in yeast: alteration by multiple heterozygosities. Science 237, 1459–1465 (1987)
Chen, W. & Jinks-Robertson, S. The role of the mismatch repair machinery in regulating mitotic and meiotic recombination between diverged sequences in yeast. Genetics 151, 1299–1313 (1999)
Weiner, B. M. & Kleckner, N. Chromosome pairing via multiple interstitial interactions before and during meiosis in yeast. Cell 77, 977–991 (1994)
Rockmill, B., Sym, M., Scherthan, H. & Roeder, G. S. Roles for two RecA homologs in promoting meiotic chromosome synapsis. Genes Dev. 9, 2684–2695 (1995)
David, L. et al. A high-resolution map of transcription in the yeast genome. Proc. Natl Acad. Sci. USA 103, 5320–5325 (2006)
Huber, W. et al. Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18 (suppl. 1). S96–S104 (2002)
Goldstein, A. L. & McCusker, J. H. Three new dominant drug resistance cassettes for gene disruption in Saccharomyces cerevisiae . Yeast 15, 1541–1553 (1999)
Slater, G. S. & Birney, E. Automated generation of heuristics for biological sequence comparison. BMC Bioinformatics 6, 31 (2005)
Wei, W. et al. Genome sequencing and comparative analysis of Saccharomyces cerevisiae strain YJM789. Proc. Natl Acad. Sci. USA 104, 12825–12830 (2007)
Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004)
Acknowledgements
We thank S. Clauder-Münster, M. Granovskaia, M. Sieber, T. Bähr-Ivacevic, M. Nguyen, V. Benes, Z. Xu, L. Ettwiller, P. McGettigan and the EMBL Genomics Core Facility for technical help; M. Knop for discussions; A. Akhtar, A. Ladurner, A. De Luna and M. Knop for critical comments on the manuscript; E. Louis, R. Durbin and D. Carter for making data from the Saccharomyces Genome Resequencing Project available; and the contributors to the Bioconductor (http://www.bioconductor.org) and R (http://www.R-project.org) projects for making their software available. This work was supported by grants to L.M.S. from the National Institutes of Health and the Deutsche Forschungsgemeinschaft, and to W.H. from the Human Frontier Science Program; and by a Darwin Trust’s Jeff Shell Scholarship awarded to E.M.
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Supplementary Information 1
This file contains Supplementary Methods, Supplementary Discussion, Supplementary Figures 1-14 with Legends and Supplementary Tables 1-5. (PDF 4570 kb)
Supplementary Information 2
This archive contains Supplementary Data, including whole genome tetrad plots, genotype calls for all spores, genotype summary statistics for wildtype spores, inferred recombination events, CO, NCO and overall recombination hot spots, and intermarker interval statistics. The details for files in this folder are given in Supplementary Table 5 within the Supplementary Information file. (ZIP 6762 kb)
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Mancera, E., Bourgon, R., Brozzi, A. et al. High-resolution mapping of meiotic crossovers and non-crossovers in yeast. Nature 454, 479–485 (2008). https://doi.org/10.1038/nature07135
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DOI: https://doi.org/10.1038/nature07135
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